Vous êtes sur la page 1sur 14

British Journal of Anaesthesia 107 (S1): i27i40 (2011)

doi:10.1093/bja/aer358

CLINICAL PRACTICE

Multimodal therapies for postoperative nausea and vomiting,


and pain
A. Chandrakantan* and P. S. A. Glass
Department of Anesthesiology, Stony Brook University Medical Center, Stony Brook, NY, USA
* Corresponding author. E-mail: arvind.chandrakantan@stonybrook.edu

Editors key points

Multimodal approaches to both


PONV and pain have been shown
to improve treatment efficacy
and reduce side-effects for
high-risk patients undergoing
surgical procedures.
These approaches integrate
both pharmacological and
non-pharmacological
interventions made before
operation, intraoperatively, and
after operation.

Keywords: nausea, postoperative; pain, postoperative; vomiting, postoperative

Postoperative nausea and vomiting


While multiple advances have been made in the last several
years in minimizing adverse outcomes after anaesthesia,
patients continue to rank nausea/vomiting as their most undesirable surgical outcome.1 2 While the incidence of postoperative nausea and vomiting (PONV) varies considerably
in both the inpatient and outpatient setting,3 6 studies indicate that the incidence of nausea ranges from 22% to 38%7
and the incidence of vomiting ranges from 12% to 26%.7
Multiple risk factors have been identified that increase the
incidence of PONV. The incidence of PONV in high-risk
patients is much higher (60 70%).8 The administration of
antiemetic drugs reduces this incidence, especially the judicious use of multiple antiemetics.9 Post-discharge nausea
and vomiting (PDNV) defined from 24 h post-discharge up
to 72 h has an incidence of up to 55%.5 10 12 It appears
that the risk factors for PDNV are different from those for
PONV.13
The multimodal approach of using more than one antiemetic was initially conceived and described due to the
limited effects of single-drug therapy14 and the finding that

multiple drug therapies resulted in a lower incidence of


PONV.15 While numerous trials have validated the utility of
this methodology, it should be understood that the multimodal approach extends far beyond intraoperative pharmacotherapy and starts with non-pharmacological interventions in
the preoperative area.16

Identification of risk factors for PONV


Several factors such as female gender and history of
PONV/motion sickness were identified retrospectively as
early as 196017 as risk factors for PONV. In 1993, a
study was performed using logistic regression analysis to
prospectively look at factors for PONV in a small cohort
of patients.18 Subsequently, Apfel and colleagues8 identified four risk factors that form the basis for the Apfel
scoring system: female gender, history of PONV/motion
sickness, non-smoking status, and use of postoperative
opioids. Each risk factor increases the likelihood of PONV
by 18 22%.8 Identification of baseline risk using the
Apfel criteria is important, since an increase in risk

& The Author [2011]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved.
For Permissions, please email: journals.permissions@oup.com

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

Postoperative nausea and


vomiting along with pain are
among the major perioperative
concerns of most surgical
patients and their anaesthetists.

Summary. Postoperative nausea and vomiting (PONV) and pain are two of the major
concerns for patients presenting for surgery. The causes of PONV are multifactorial
and can largely be categorized as patient risk factors, anaesthetic technique, and
surgical procedure. Antiemetics work on several different receptor sites to prevent
or treat PONV. This is probably why numerous studies have now demonstrated
that using more than one antiemetic is usually more effective and results in fewer
side-effects than simply increasing the dose of a single antiemetic. A multimodal
approach to PONV should not be limited to drug therapy alone but should involve
a holistic approach starting before operation and continuing intraoperatively with
risk reduction strategies to which are added prophylactic antiemetics according to
the assessed patient risk for PONV. With the increasing understanding of the
pathophysiology of acute pain, especially the occurrence of peripheral and central
hypersensitization, it is unlikely that a single drug or intervention is sufficiently
broad in its action to be adequately effective, especially with moderate or greater
pain. Although morphine and its congeners are usually the foundation of pain
management regimens, as their dose increases so does the incidence of sideeffects. Thus, the approach for the management of acute postoperative pain is to
use multiple drugs or modalities (e.g. regional anaesthesia) to maximize pain
relief and reduce side-effects.

BJA

Pathophysiology of PONV
Emesis is believed to be governed by the emesis centre in the
brain, which receives several afferent inputs (Fig. 1). Vagal
input from the gut can activate the emetic centre, and also
afferent action from the chemoreceptor trigger zone (CTZ).
The CTZ sits outside the blood brain barrier and contains
several different receptors that modulate its activity. Most
antiemetic medications act by either a direct or indirect
antagonizing of emetogenic substances on receptors in
the CTZ.
As there are several receptor systems involved in the development and treatment of PONV, it seems obvious that a
combination of drugs acting at the different receptors
would have greater efficacy than a single drug. Increasing
the dose of a single class of drug does not necessarily decrease the incidence of PONV, especially in patients with
risk factors.32 33 Also, the incidence of side-effects increases
as the dose increases in many drug classes (Table 1).34 The
multimodal technique therefore offers the benefits of
enhanced PONV reduction with a lower incidence of
side-effects.
Intuitively, the combined effects of drugs should be synergistic since each antiemetic intervention has a different
mode of action. However, current data for the agents available indicate that the effects are simply additive.9 35 36 This
observation underscores the importance of risk-stratifying
patients as noted above and a holistic approach emphasizing both pharmacological and non-pharmacological
therapies.

i28

Approach to multimodal therapy


Broadly, the multimodal approach constitutes both pharmacological and non-pharmacological therapies, which commences in the preoperative area and continues until
discharge of the patient. In the preoperative area, minimizing
anxiety is important. Anxiolysis with benzodiazepines has
been shown to reduce PONV in several small studies.37 38
Other interventions to minimize anxiety include optimizing information provided to the patient, a patient-friendly facility
layout, and positive and compassionate interactions with
staff. All of these interventions help minimize anxiety and
likely reduce the incidence of PONV due to its impact on PONV.
Preoperative dexamethasone reduces the incidence of
PONV.39 Aprepitant (a neurokinin-1 antagonist) administered
before anaesthesia is effective in reducing both vomiting and
nausea for up to 48 h after surgery.40 41 Pre-hydration with
oral carbohydrate containing clear fluids up to 2 h before
surgery also reduces PONV.42 Similarly, adequate i.v. fluid resuscitation has become part of the multimodal regimen43 44
with both crystalloids and colloids reducing PONV.45 The
choice of the type of fluid does not alter the incidence of
PONV significantly.46
The intraoperative approach starts with minimizing
factors that can increase PONV. Thus, the choice of anaesthetic is important. Inhalation anaesthetics, including
nitrous oxide (dose-dependent), are associated with an
increased risk of PONV. The use of regional anaesthesia
decreases the incidence of PONV compared with general anaesthesia.47 Although it would be ideal for patients at high
risk for PONV/PDNV, regional anaesthesia is not always available as an option. Total i.v. anaesthesia (TIVA) decreases the
incidence of PONV compared with inhalation anaesthetics
and N2O.43 More specifically, the use of propofol as both an
induction and maintenance agent (as TIVA) decreases the incidence of PONV,6 48 but might be associated with higher
cost.6 Propofol has direct antiemetic effects and has been
used after operation to treat PONV at doses of 1020 mg.
The minimum effective concentration of propofol for PONV
is 300 ng ml21.49 As patients usually wake up at propofol
concentrations of 1000 2000 ng ml21, the antiemetic
effect of propofol administered intraoperatively lasts for up
to 30 min after operation.
Analgesia is a key component of intraoperative anaesthesia, with opioids as the mainstay of treatment. However,
increasing intraoperative and postoperative opioid administration is associated with a much higher risk of PONV.28
Short-acting opioids do not increase the incidence of
PONV50 when used as part of a TIVA regimen, but do not
offer postoperative analgesia. Pain itself increases PONV,
and thus the objective is to create the optimal balance
between opioid administration and pain relief. There are
several analgesic alternatives to opioids that have become
available for i.v. administration in the last few years. Reducing the amount of opioids administered while obtaining
good pain relief is the ultimate objective. Non-steroidal
anti-inflammatory drugs (NSAIDs) decrease PONV compared

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

factors increases the number of subsequent therapies


required.9
Although Apfel defined the risk criteria with the largest
impact on PONV, multiple other risk factors have been identified. These can be broadly divided into three categories:
patient risk factors, anaesthetic technique, and surgical procedure. Patient risk factors include female gender from
puberty, non-smoking status, previous history of PONV/
motion sickness, and genetic predisposition.3 19 22 Anaesthetic technique includes the use of inhalation agents,
nitrous oxide, large-dose neostigmine, and intraoperative
and postoperative opioid use.9 19 23 28 Surgical factors
include longer duration of surgery and different types of surgeries.8 20 22 29 However, whether longer surgeries are directly causal is difficult to prove, since higher doses of opioids
and longer exposure to inhalation anaesthetics (MAC-hours)
are likely to occur and are known risk factors of PONV.9 20 Although risk factors are well defined for the population and
are used to plan antiemetic therapy for a given individual,
they unfortunately are not highly predictive.30
In children, there are fewer data than in adults regarding
risk factors. However, Eberhart and colleagues31 identified
four risk factors: duration of surgery .30 min, age .3 yr,
strabismus surgery, and history of postoperative vomiting in
a parent, sibling, or the patient.

Chandrakantan and Glass

BJA

Multimodal therapies for PONV and pain

The chemoreceptor trigger zone and emetic centre


Antagonist
5-HT3RAs

Promethazine

5-HT3

Histamine

Droperidol

Atropine

NK-1 RA

Agonist
Muscarinic Dopamine (D2) Substance P

Area
postrema

Receptor site

Nitrogen mustard
Cisplatin
Digoxin glycoside

Chemoreceptor
trigger
zone
(CTZ)

Opioid, analgesics
Vestibular portion
of 8th nerve
Mediastinum

Emetic
centre

N2O

?
Vag

us

GI tract distension
Higher centres (vision, taste)
Pharynx

Fig 1 CTZ and emetic centre. With permission from Watcha and White.73

Table 1 Side-effects of commonly used antiemetics by drug class


Drug class

Side-effects

Serotonin
antagonists

Headache, diarrhoea, constipation,


arrhythmia

Neurokinin
inhibitors

Dizziness, diarrhoea, headaches, weakness

Steroids

Dizziness, mood changes, nervousness

Antihistamines

Confusion, drying of mucosal membranes,


sedation, urinary retention

Butyrophenones

Prolonged QT interval (at doses 0.1 mg


kg21), hypotension, tachycardia,
extra-pyramidal symptoms

Benzodiazepines

Sedation, disorientation

with opioids in numerous studies.51 53 There are clear data


for the opioid-sparing effects of NSAIDs and consequent reduction in PONV.54 Small doses of i.v. ketamine also provide
opioid-sparing55 with a trend towards reducing PONV.56 The
opioid-sparing effects described above have a dual role of
both reducing the incidence of PONV and enhancing overall
pain management as described for multimodal analgesia
below.
Reversal of neuromuscular block is required for many
types of surgeries. Although multiple authors23 have demonstrated that high-dose neostigmine increases the risk of
PONV, a recent meta-analysis suggests no increased risk

with neostigmine use.57 This issue remains unclear, and


more study is needed on this issue.
Intraoperative antiemetics form the cornerstone of antiemetic therapy16 (Fig. 2). Apfel and colleagues9 demonstrated that using one or more antiemetic therapies (up
to 4) decrease the incidence of nausea and vomiting
significantly (Fig. 3). This study showed that with each additionally administered antiemetic, the risk of PONV was
further reduced by 30% (the so-called rule of 1/3). This extremely large study provides the foundation demonstrating
the validity of the multimodal model.58 Numerous studies
have shown that two antiemetic therapies significantly decrease the incidence of PONV compared with single-drug
prophylaxis in high-risk surgical populations.59 60 Although
there are data demonstrating the efficacy of different antiemetic therapies, too much of a good thing can be counterproductive. Recent data suggest that aprepitant, when
added to three different antiemetics, might actually increase
the incidence of PONV.61 With a minimal cost and sideeffects of the majority of antiemetics available, a more
liberal approach than suggested by the Apfel criteria or the
SAMBA (Society for Ambulatory Anesthesiology) guidelines
has been proposed.62
Acustimulation at the P6 acupoint has been shown to be effective in preventing PONV.63 64 A meta-analysis of acustimulation in pregnant patients has shown similar efficacy.65 As part
of a multimodal regime, acustimulation provides a further 30%
reduction of PONV when combined with 4 mg ondansetron (i.e.
similar efficacy as a second antiemetic).66 There are smaller

i29

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

Parvicellular
reticular
formation

BJA

Chandrakantan and Glass

Adult risk factors


Patient related
History of PONV/motion sickness
Female gender
Non-smoker

Children risk factors


Environmental
Surgery >30 min
Postop opioids
Age >3 years
Emetogenic surgery
Strabismus surgery
(type and duration)
History of POV/relative to PONV

Consider

Costeffectiveness

Patient preferences
Fear of PONV
Frequency of
PONV causing
headaches/migraine

Reducing baseline risks


Avoidance/minimization of:
Nitrous oxide
Volatile anesthetics
High-dose neostigmine
Post-op opioids

Level of risk
0 RF=10%
1 RF=10%20%
2 RF=30%40%
3 RF=50%60%
4 RF=70%80%

Patient risk

Medium
Pick 1 or 2 interventions for adults
Pick 2 interventions for children

Propofol
Anesthesia

Dexamethasone

Regional
Anesthesia
Droperidol
or Haloperidol

5-HT3
antagonist

Non-pharmacological:
Acupuncture

High
2 interventions/
multi approach

Portfolio of
prophylaxis
and treatment

Promethazine
Prochlorperazine
Perphenazine
Propofol in
PACU
(rescue only)

Scopolamine
Ephedrine

Dimenhydrinate

Treatment options
If prophylaxis fails or was not received: use antiemetic
from different class than prophylactic agent
Readminister only if >6 h after PACU: do not
readminister dexamethasone or scopolamine

Use droperidol in children only if other


therapy has failed and patient is being
admitted to hospital
Some of the drugs may not have been studied
or approved by the FDA for use in children.

Fig 2 Algorithm for management of PONV. SAMBA guidelines for PONV from Gan and colleagues16 with permission.

studies that demonstrate that acupuncture decreases PONV


over 24 h;67 however, data for PDNV are lacking.
PDNV is quite common after outpatient surgery.5 However,
risk factors for PDNV are likely to be quite different from those
of PONV.13 Thus, the antiemetics that are effective and the
impact of multimodal therapy are also likely to be quite different. In a meta-analysis of PDNV, ondansetron and dexamethasone were more effective than placebo. However,

i30

droperidol did not seem effective for PDNV prophylaxis. In


the few combination studies reviewed in this article, a combination of two drugs was more effective than a single drug.
For example, the number needed to treat (NNT) with ondansetron 4 mg was 13, while for a combination of two antiemetics, the NNT was about 5. The authors concluded that
the routine use of two or more antiemetics for PDNV in highrisk patients is justified.11 The data on the efficacy of specific

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

Low
Wait and see

BJA

Multimodal therapies for PONV and pain

Volatile
anesthetic
and N2O

70

Volatile
anesthetic
and air

Propofol
and N2O

Propofol
and air

Incidence of postoperative
nausea and vomiting (%)

60
50
40
30
20
10

2 3
0 1 2
No. of antiemetics

Fig 3 Effect of multiple antiemetic therapies. With permission from Apfel and colleagues. & Massachusetts Medical Society.9

antiemetics and their combination are still lacking, so definitive conclusions are difficult to make at present.

Conclusions
A planned multimodal algorithm starting in the preoperative
area can significantly reduce the incidence of PONV. This
includes both a strategy for risk assessment, risk reduction,
and therapy targeted at matching the risk with the number
of antiemetics administered. Most patients present with at
least one Apfel criteria risk factor. As the cost both in
money and side-effects is small with present antiemetics,
the authors preference is to start with a minimum of two
antiemetics (generally dexamethasone 4 mg soon after induction and ondansetron 4 mg 20 min before the end of
surgery). To this are added additional antiemetics depending
on other risk factors. Unfortunately, the efficacy of the multimodal technique in preventing PDNV remains unclear. Although many of the same risk factors carry through to
discharge, it is uncertain whether a similar multimodal approach to PDNV is similarly effective.

Multimodal approach to pain management


Despite advancements in the understanding of the pathophysiology of pain and pharmacotherapeutics, pain remains
poorly treated in both the inpatient and ambulatory
setting.68 The importance of quantifying and treating acute
postoperative pain is not only because of how unpleasant it
is, but also because, if poorly treated, there is a risk for the
development of chronic pain and its incumbent morbidity.69
Besides concerns of prolonged recovery and rehabilitation,
pain still ranks among the highest patient and physician

concerns for undesirable surgical outcomes.1 2 The physiological consequences of pain can be quite deleterious to
the patient. The incidence of mild-to-moderate pain after a
variety of moderately invasive surgeries is about 6265%68
and the visual analogue scale remains .4 in about 10% of
patients 7 days after discharge.70 However, the incidence of
the progression to chronic pain varies by surgery.71 Today,
acute postoperative pain is recognized to have two components, an earlier inflammatory component and a later neuropathic component. Just alleviating the inflammatory
component in susceptible patients might not be sufficient;
addressing the neuropathic pain component can be equally
important in the prevention of chronic pain.72
Similar to the multimodal approach to PONV, the multimodal approach to pain management was conceived due
to limitations in single-drug therapy, namely opioids and
NSAIDs,73 74 for which there is an increasing incidence of
side-effects with increasing doses. Kehlet and Dahl75 were
the first to suggest that combining medications acting
through different mechanisms lowers doses of analgesics,
pain is better controlled, and there is a lower incidence of
side-effects. This has since been demonstrated in multiple
studies.76 80 Again similar to PONV, the multimodal approach to pain management starts in the preoperative area.

Identification of risk factors for pain


Unlike PONV with the Apfel criteria, clearly quantifiable risk
factors for postoperative pain have not been identified.
While qualitative risk factors do exist, basing analgesic
therapy on the number of risk factors is not feasible.
However, identification of risk factors and assessment is

i31

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

BJA

Pathophysiology of pain
Although there are multiple definitions of pain, most experts
agree that it is primarily a sensory experience.72 There are
two major components that contribute to perioperative
pain, namely inflammatory and neuropathic pain. Both of
these states share multiple common features and can be
experienced either jointly or separately.93
A nociceptive stimulus from any source, whether thermal,
mechanical, or otherwise, causes a release of multiple inflammatory substances in the affected tissue (Fig. 4). This
leads to sensitization of nerves that supply the affected
area, a phenomenon known as peripheral sensitization.
Owing to afferent input to the central nervous system
(CNS), the CNS also becomes sensitized, a phenomenon
known as central sensitization. Both forms of sensitization
are mediated through numerous neurotransmitters and
feedback systems (Figs 4 and 5). These mechanisms are
mainly protective in nature. The mechanisms involved in centrally mediated pain transmission are demonstrated in

i32

Figure 5. In general, as tissue heals the physiological


changes ensuing from inflammatory pain resolve.
The progression from acute inflammatory pain to chronic
neuropathic pain is poorly understood. There are three
mechanisms that are central to the mediation of chronic
neuropathic pain. First is the peripheral component with
release of multiple inflammatory mediators responsible for
the so-called positive symptoms, including hypersensitivity,
allodynia, and erythema. Second is the central component,
through the wind-up mechanism, that is mediated through
the dorsal horn neurones and involves several areas of the
CNS.94 Third is the concept of central plasticity, in which
both an excess of excitatory transmission and a loss of inhibitory transmission lead to an unfettered barrage of CNS input
from the dorsal horn of the spinal cord.95 Despite this highly
simplified model, the pathophysiology of neuropathic pain
remains poorly understood,96 and multiple mechanisms
remain to be elucidated.
The concept of pre-emptive analgesia focuses primarily on
the early timing of analgesic therapy, whereas preventive analgesia focuses primarily on timing, duration, and efficacy of
analgesic therapy.97 A significant body of literature supporting pre-emptive analgesia has been withdrawn, thus creating
ambiguity about the efficacy of this technique. The preventive model of analgesia has demonstrated clinical benefit,98
and is the basis for the multimodal technique. The multimodal technique preserves total body nitrogen and
enhances postoperative recovery and rehabilitation.99 100

Multimodal approach to pain management


Opioids still remain the mainstay of perioperative pain management (Fig. 6). While their judicious use offers analgesia
through central and peripheral mechanisms, they are
associated with many side-effects including an increased incidence of PONV, sedation, drowsiness, and pruritus, which
delay discharge and add cost to postoperative care.101 102
Additionally, there are animal data that demonstrate potentiation by opioids of tumour growth and tumour angiogenesis.103 It is believed that this is regulated through the
m-opioid receptor.104 A corollary for this concept has been
drawn in breast and prostate cancer studies in two retrospective studies. When regional anaesthesia was used instead of
postoperative opioid analgesia, the recurrence rate and metastases for breast cancer were lower, and the risk of prostate
cancer recurrence was similarly decreased.105 106
NSAIDs, including COX-2 inhibitors, provide opioid-sparing
(reduced opioid dosing requirements) and reduce some
opioid-related side-effects.52 107 Where bleeding is a
concern for the surgical procedure (e.g. tonsillectomies),
the use of non-selective NSAIDs should be avoided.25 108 A
meta-analysis suggested that the safety profile of selective
COX-2 inhibitors in this setting can be useful.109 After the
withdrawal of several COX-2 products due to their long-term
cardiovascular risks, their use in the acute postoperative
setting was also called into question. An editorial suggests
that there still clearly remains immediate and intermediate

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

still of paramount importance to minimize acute postoperative pain and progression to chronic pain.
Many patients who present for surgical procedures do so
because of pain, and preoperative pain is a known risk
factor for postoperative pain.69 Therefore, a thorough preoperative assessment is essential. As alluded to previously,
certain surgeries, namely Caesarean section, coronary
artery bypass grafting, inguinal hernia repair, breast
surgery, thoracotomy, and amputation, have a higher incidence of progression to chronic pain.72 81
Preoperative anxiety has been correlated with increased
postoperative pain.82 83 Despite this, the effect of preoperative
benzodiazepine therapy on postoperative pain is unclear.84 85
However, the incidence of side-effects from administration of
benzodiazepines is low. Preoperative lorazepam results in
reduced pain after abdominal hysterectomy,86 and patients
self-reported improvement in at least one other study with administration of preoperative midazolam.87
There have been several studies on genetic factors predisposing to both acute postoperative pain and its progression
to chronic pain.88 These are small studies without sufficient
data to allow for individual patient stratification in the clinical
setting.
Opioid tolerance stemming from long-term chronic opioid
use is an important risk factor for increasing the complexity
of treating postoperative acute pain. Thus, a quantification of
opioid use in addition to bioavailability is important in the
perioperative setting. Opioid management in these patients
remains controversial; however, multimodal analgesia has
been used successfully.89
Females require more analgesics90 and are also more susceptible to developing chronic pain.83 Several of the surgeries
above are more common in women, and multimodal analgesia has been demonstrated to reduce the progression to
chronic pain in these patients.91 92

Chandrakantan and Glass

BJA

Multimodal therapies for PONV and pain

Capillary

Astrocyte

Compromised
coupling between
synaptic activity
and perfusion
Oligodendroglia

MCP-1
INF-,TNF-,IL-1

PGs
IL-1, IL-6
TNF-
NO (RNS)
H2O2(ROS)

Glutathione

Glutathione
precursors

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

Glycogen
Glutathione

Lactate
during peak
synaptic
activity

Microglia

IDO

BDNF

Glu
Apoptosis

Quinolinic
Acid

KA

Tryptophane

5HT

TNF-
D-Serine
ATP

Demyelination
EAAT
mGlu

Excitotoxicity

Glu
AMPA

Glu
NMDA
BDNF

Pre-synaptic nerve ending

Post-synaptic nerve ending

Fig 4 Microglia and inflammation. With permission from Maletic and colleagues (2009).147

benefit from COX-2 inhibition given for short durations such


as postoperative pain, although long-term benefit remains
unclear.110 There is no increased cardiovascular risk in
patients receiving short-term selective COX-2 inhibitors
after non-cardiac surgery.111 In one major study, when oral
ibuprofen (non-selective NSAID) was compared with celecoxib (COX-2 inhibitor), they were both similarly efficacious
in reduction of postoperative pain, constipation, and early

need for rescue analgesia.112 Thus, where bleeding is of


minimal risk, non-selective NSAIDs are most appropriate,
but where bleeding is a concern, a COX-2 inhibitor should
be used.
Ketamine, because of its unique mode of action, has been
studied extensively, especially in the orthopaedic literature.
Small doses (0.15 mg kg21 i.v.) improve recovery after outpatient arthroscopy.113 In a large analysis, ketamine was

i33

BJA

Chandrakantan and Glass

Dorsal horn neuron


Central terminal of
primary sensory neutron

PGE2
EP
Trk B

BDNF
Tyr
S/T

NMDA
Activity
Glutamate
aspartate

COX-2

src

AMPA

PKC

S/T

Ca2+

+
PKA

mGluR

IP3

NK1

NOS
NO

Fig 5 Mechanisms of central pain transmission. Reproduced from Costigan and Woolf (2000)148 with permission from Elsevier.

Pharmacological
intervention along
pain pathways

Opioids, APAP,
Clonidine, Ketamine,
Gabapentin, Tricyclics

5. Perception

6. CNS responses
Muscle relaxants,
Beta blockers
1. Transduction

4. Modulation

NSAIDS, COX-2 Inhibitors,


Anti-Histamines, Topical
local anesthetics

Opioids, Clonidine
APAP, COX-2 Inhibitors,
Ketamine Gabapentin

PAIN
2. Conduction
Peripheral nerve block
local anesthetics

3. Transmission
Epidural block
local anesthetics

Fig 6 Multimodal approach to pain management. With permission from Raymond Sinatra, MD.

i34

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

Sub P

Multimodal therapies for PONV and pain

Regional anaesthesia, whether neuraxial, via a peripheral


nerve block, or both, is an important component of a multimodal regimen. When using regional anaesthesia, it is not
only the modality, but also the duration of therapy that is important. Local anaesthetic administration into the wound has
been studied as part of multimodal regimens in laparoscopic
surgeries. Although there are benefits in the immediate postoperative period (up to 4 h), these differences are less pronounced over time.130 131 The results from single-shot
peripheral nerve block studies also substantiate this effect,
with early postoperative pain relief, but a high percentage
of patients require adjuvant pain therapy at 24 h and up to
7 days.132 When continuous perineural catheters (from 2 to
7 days) were used in combination with NSAIDs, postoperative
analgesia beyond 24 h was very good.133 Clonidine, when
added as part of a single-shot upper extremity nerve block,
enhances the duration of action of the block.134
In a meta-analysis, the use of regional anaesthesia
decreased all-cause mortality and multiple morbidity
indices.135 Therefore, the use of neuraxial anaesthesia
when appropriate might have several effects independent
of pain control. Epidural anaesthesia (continued after operation) combined with general anaesthesia was superior to
general anaesthesia alone in multiple outcomes.136 There
are also data to indicate that in thoracotomy surgeries,
which are at high risk for chronic pain, the use of perioperative epidural analgesia decreases the incidence of chronic
pain.137 Neuraxial analgesia is not beneficial in reducing
the progression to chronic pain for all high-risk surgeries;
however, the studies are small and further data are
needed.138 Spinal anaesthesia compared with general anaesthesia for hysterectomy decreased the incidence of
chronic pain in one retrospective analysis.139 Nitrous oxide
has also been suggested to reduce the incidence of progression to chronic pain; however, further study is needed.140
There is value to using several pharmacological agents as
part of a neuraxial block. The addition of clonidine to a bupivacaine/fentanyl solution significantly reduced pain, but
side-effects were noted to be dose-dependent for increasing
clonidine.141 Concerns over hypotension have limited use of
clonidine in the obstetric population. However, at least one
study did not demonstrate adverse sequelae due to this.142
The optimal combination of bupivacaine, fentanyl, clonidine,
and infusion rate has been determined. The combination
that provided the greatest pain relief at the lowest infusion
rate was 9 mg h21 bupivacaine, 21 mg h21 fentanyl, and 5
mg h21 clonidine infused at 7 ml h21.143
Postoperative pain can also be reduced by nonpharmacological adjuvants. Transcutaneous electrical nerve
stimulation (TENS), when used at sub-noxious frequency
over the wound area, reduces postoperative analgesic consumption.144 Peri- and postoperative wound cooling significantly reduces postoperative analgesic consumption
without an increase in wound infections.145 Studies have
suggested a role of heat in peripheral sensitization.146
However, further studies are needed for all of the above modalities before definitive conclusions can be drawn.

i35

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

opioid-sparing with a low incidence of side-effects.55 When


i.v. ketamine was added into a multimodal regimen that
included postoperative epidural analgesia, the progression
to chronic pain was reduced.114 Also, ketamine added to
an epidural multimodal regimen improved analgesia, demonstrating that its efficacy is not confined to the i.v. route
alone.115 The effects of oral ketamine on chronic pain are
complex, and there are varying degrees of efficacy depending on the type of chronic pain.116 Early administration of
ketamine seems important in the prevention of
chronic pain. Dextromethorphan is another N-methylD-aspartate-type
glutamate receptor antagonist that
prevents central wind up and has other antinociceptive
mechanisms of action. Despite a fair number of studies on
its use, the results remain conflicting.101
Gabapentin has been studied in multiple small trials that
have been analysed in several large meta-analyses. Despite
demonstrating opioid-sparing effects, superior acute postoperative analgesia, and a decrease in pain scores, a decrease
in opioid-related side-effects was not noted.117 118 The most
favourable data with the fewest side-effects came from a
single dose of 1200 mg of gabapentin given in the preoperative
setting.119 These effects have only been shown in the acute
postoperative setting; gabapentin has not been shown to decrease the progression to chronic pain.120 121 Pregabalin was
evaluated as part of a multimodal regimen for total knee
arthroplasty surgery, and was continued for 14 days into the
postoperative period. There was a statistically significant reduction in chronic pain at 6 months; however, there was immediate peri- and postoperative confusion- and sedation-related
issues that were attributed to dosing.122 Similar to COX-2 inhibitors, several retracted articles on pregabalin bring its routine
use into question as part of a multimodal regimen, and thus
more studies are warranted. One might expect its actions to
be similar to gabapentin. The antidepressant venlafaxine,
when given before operation/perioperatively, reduced progression to post-mastectomy pain; however, the study did
not use a multimodal analgesic regimen.123 Therefore, more
studies are needed with antidepressants before definitive conclusions can be made as to their role in preventive analgesia.
Two of the a-2 agonists have been studied as part of the
multimodal regimen: dexmedetomidine and clonidine. Dexmedetomidine has shown to reduce opioid-related sideeffects, enhance analgesia, and was devoid of side-effects
when used for acute postoperative pain control as part of
an i.v. patient-controlled analgesia regime.124 When used
for postoperative analgesia and recovery, dexmedetomidine
plus morphine compared with morphine alone demonstrated
an additive effect.125 Dexmedetomidine as part of a perioperative analgesic regimen decreases opioid requirements,
PONV, and postoperative stay.126 I.V. clonidine, on the
other hand, has not demonstrated any efficacy in the treatment of postoperative pain.127 128 However, when used via
the neuraxial route, clonidine as part of a multimodal
regime is effective in reducing both acute postoperative
pain and progression to chronic pain.129

BJA

BJA
References
1

10
11

Conclusions
A planned multimodal approach to pain management can
significantly reduce acute postoperative pain and its progression to chronic pain. Blockade of both peripheral and central
sensitization through the use of multiple agents and
approaches is critical. The number of agents is important;
however, the duration of therapy is also critical to ensure
that analgesia is continued into the postoperative period to
ensure mobilization and recovery. While there are data to
support several individual agents and modalities in reducing
progression to chronic pain, further study is needed to delineate the exact risk factors and optimal drug combinations in
preventing chronic pain.

Conflict of interest
None declared.

Funding
The authors have no external sources of funding related to
this article.

i36

12

13

14

15

16

17

Macario A, Weinger M, Carney S, Kim A. Which clinical anesthesia


outcomes are important to avoid? The perspective of patients.
Anesth Analg 1999; 89: 652 8
Macario A, Weinger M, Truong P, Lee M. Which clinical anesthesia
outcomes are both common and important to avoid? The perspective of a panel of expert anesthesiologists. Anesth Analg
1999; 88: 108591
Apfel CC, Kranke P, Katz MH, et al. Volatile anaesthetics may be
the main cause of early but not delayed postoperative vomiting:
a randomized controlled trial of factorial design. Br J Anaesth
2002; 88: 65968
Chen HL, Wong CS, Ho ST, Chang FL, Hsu CH, Wu CT. A lethal pulmonary embolism during percutaneous vertebroplasty. Anesth
Analg 2002; 95: 10602, table of contents
Wu CL, Berenholtz SM, Pronovost PJ, Fleisher LA. Systematic
review and analysis of postdischarge symptoms after outpatient
surgery. Anesthesiology 2002; 96: 994 1003
Visser K, Hassink EA, Bonsel GJ, Moen J, Kalkman CJ. Randomized controlled trial of total intravenous anesthesia with propofol versus inhalation anesthesia with isoflurane-nitrous
oxide: postoperative nausea with vomiting and economic analysis. Anesthesiology 2001; 95: 616 26
Cohen MM, Duncan PG, DeBoer DP, Tweed WA. The postoperative
interview: assessing risk factors for nausea and vomiting. Anesth
Analg 1994; 78: 7 16
Apfel CC, Laara E, Koivuranta M, Greim CA, Roewer N. A simplified risk score for predicting postoperative nausea and vomiting:
conclusions from cross-validations between two centers. Anesthesiology 1999; 91: 693700
Apfel CC, Korttila K, Abdalla M, et al. A factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med 2004; 350: 244151
Lichtor JL, Glass PS. Were tired of waiting. Anesth Analg 2008;
107: 353 5
Gupta A, Wu CL, Elkassabany N, Krug CE, Parker SD, Fleisher LA.
Does the routine prophylactic use of antiemetics affect the incidence of postdischarge nausea and vomiting following ambulatory surgery?: A systematic review of randomized controlled
trials. Anesthesiology 2003; 99: 48895
Carroll NV, Miederhoff P, Cox FM, Hirsch JD. Postoperative nausea
and vomiting after discharge from outpatient surgery centers.
Anesth Analg 1995; 80: 903 9
White PF, Sacan O, Nuangchamnong N, Sun T, Eng MR. The
relationship between patient risk factors and early versus late
postoperative emetic symptoms. Anesth Analg 2008; 107:
459 63
Habib AS, Gan TJ. Combination therapy for postoperative nausea
and vomitinga more effective prophylaxis? Ambul Surg 2001;
9: 59 71
Eberhart LH, Morin AM, Bothner U, Georgieff M. Droperidol and
5-HT3-receptor antagonists, alone or in combination, for
prophylaxis of postoperative nausea and vomiting. A
meta-analysis of randomised controlled trials. Acta Anaesthesiol
Scand 2000; 44: 1252 7
Gan TJ, Meyer TA, Apfel CC, et al. Society for Ambulatory Anesthesia guidelines for the management of postoperative
nausea and vomiting. Anesth Analg 2007; 105: 1615 28, table
of contents
Bellville JW, Bross ID, Howland WS. Postoperative nausea and
vomiting. IV. Factors related to postoperative nausea and vomiting. Anesthesiology 1960; 21: 18693

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

In summary, the anaesthetic pain regime should start in


the preoperative area with patient assessment and detailed
communication with the surgeon about the type of surgery
and the proposed approach. The more qualitative risk factors
a patient possesses, the more aggressive the anaesthesiologist should be in their preventative pain management. Regional anaesthesia, either neuraxial or peripheral nerve block,
should always be considered where feasible. Breakthrough
pain is well described in the chronic pain and cancer literature,
and it similarly occurs in the acute postoperative situation. It is
best managed with a rapid onset, short-lasting agent (e.g. fentanyl in the recovery room) or an agent of a different class than
those previously administered.
For expectant mild pain from minor surgery, the authors
recommend acetaminophen, NSAIDs, or both, local anaesthetic wound infiltration, and intraoperative opioid therapy.
Non-pharmacological therapy (e.g. TENS, cooling packs)
should also be used when appropriate after operation.
For expected moderate pain, the authors suggest two to
three agents to be used intraoperatively, including regional
anaesthesia. A combination of opioids and NSAIDs should
also be considered for postoperative pain management.
For expected severe pain, the authors suggest that regional anaesthesia be strongly considered unless contraindicated, with a multiagent infusion and leaving the regional
catheter in place. Intraoperative management should also
consist of aggressive multimodal agent regimen, with
prompt attention and treatment of postoperative pain.
In patients with a history of chronic opioid use or where
the risk of chronic pain is high, both ketamine and regional
anaesthesia should be considered both intraoperatively and
after operation.

Chandrakantan and Glass

Multimodal therapies for PONV and pain

36 Rosow CE, Haspel KL, Smith SE, Grecu L, Bittner EA. Haloperidol
versus ondansetron for prophylaxis of postoperative nausea and
vomiting. Anesth Analg 2008; 106: 14079, table of contents
37 Fujii Y, Itakura M. A prospective, randomized, double-blind,
placebo-controlled study to assess the antiemetic effects of
midazolam on postoperative nausea and vomiting in women
undergoing laparoscopic gynecologic surgery. Clin Ther 2005;
32: 1633 7
38 Jung JS, Park JS, Kim SO, et al. Prophylactic antiemetic effect of
midazolam after middle ear surgery. Otolaryngol Head Neck
Surg 2007; 137: 7536
39 Gomez-Hernandez J, Orozco-Alatorre AL, DominguezContreras M, et al. Preoperative dexamethasone reduces postoperative pain, nausea and vomiting following mastectomy for
breast cancer. BMC Cancer 2010; 10: 692
40 Diemunsch P, Gan TJ, Philip BK, et al. Single-dose aprepitant vs
ondansetron for the prevention of postoperative nausea and
vomiting: a randomized, double-blind phase III trial in patients
undergoing open abdominal surgery. Br J Anaesth 2007; 99:
202 11
41 Gan TJ, Apfel CC, Kovac A, et al. A randomized, double-blind
comparison of the NK1 antagonist, aprepitant, versus ondansetron for the prevention of postoperative nausea and vomiting.
Anesth Analg 2007; 104: 1082 9, table of contents
42 Jensen K, Kehlet H, Lund CM. Post-operative recovery profile
after laparoscopic cholecystectomy: a prospective, observational study of a multimodal anaesthetic regime. Acta Anaesthesiol
Scand 2007; 51: 464 71
43 Scuderi PE, James RL, Harris L, Mims GR III. Multimodal antiemetic management prevents early postoperative vomiting
after outpatient laparoscopy. Anesth Analg 2000; 91: 140814
44 Yogendran S, Asokumar B, Cheng DC, Chung F. A prospective
randomized double-blinded study of the effect of intravenous
fluid therapy on adverse outcomes on outpatient surgery.
Anesth Analg 1995; 80: 682 6
45 Chaudhary S, Sethi AK, Motiani P, Adatia C. Pre-operative intravenous fluid therapy with crystalloids or colloids on postoperative nausea & vomiting. Indian J Med Res 2008; 127:
577 81
46 Haentjens LL, Ghoundiwal D, Touhiri K, et al. Does infusion of
colloid influence the occurrence of postoperative nausea and
vomiting after elective surgery in women? Anesth Analg 2009;
108: 1788 93
47 Borgeat A, Ekatodramis G, Schenker CA. Postoperative nausea
and vomiting in regional anesthesia: a review. Anesthesiology
2003; 98: 530 47
48 Joo HS, Perks WJ. Sevoflurane versus propofol for anesthetic induction: a meta-analysis. Anesth Analg 2000; 91: 213 9
49 Gan TJ, Glass PS, Howell ST, Canada AT, Grant AP, Ginsberg B.
Determination of plasma concentrations of propofol associated
with 50% reduction in postoperative nausea. Anesthesiology
1997; 87: 779 84
50 Dershwitz M, Michalowski P, Chang Y, Rosow CE, Conlay LA. Postoperative nausea and vomiting after total intravenous anesthesia with propofol and remifentanil or alfentanil: how important
is the opioid? J Clin Anesth 2002; 14: 275 8
51 Shende D, Das K. Comparative effects of intravenous ketorolac
and pethidine on perioperative analgesia and postoperative
nausea and vomiting (PONV) for paediatric strabismus surgery.
Acta Anaesthesiol Scand 1999; 43: 265 9
52 Marret E, Kurdi O, Zufferey P, Bonnet F. Effects of nonsteroidal
antiinflammatory drugs on patient-controlled analgesia

i37

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

18 Palazzo M, Evans R. Logistic regression analysis of fixed patient


factors for postoperative sickness: a model for risk assessment.
Br J Anaesth 1993; 70: 13540
19 Gan TJ. Risk factors for postoperative nausea and vomiting.
Anesth Analg 2006; 102: 1884 98
20 Sinclair DR, Chung F, Mezei G. Can postoperative nausea and
vomiting be predicted? Anesthesiology 1999; 91: 109 18
21 Janicki PK, Vealey R, Liu J, Escajeda J, Postula M, Welker K.
Genome-wide association study using pooled DNA to identify
candidate markers mediating susceptibility to postoperative
nausea and vomiting. Anesthesiology 2011; 115: 54 64
22 Koivuranta M, Laara E, Snare L, Alahuhta S. A survey of postoperative nausea and vomiting. Anaesthesia 1997; 52: 4439
23 Tramer MR, Fuchs-Buder T. Omitting antagonism of neuromuscular block: effect on postoperative nausea and vomiting and
risk of residual paralysis. A systematic review. Br J Anaesth
1999; 82: 379 86
24 Sukhani R, Vazquez J, Pappas AL, Frey K, Aasen M, Slogoff S. Recovery after propofol with and without intraoperative fentanyl in
patients undergoing ambulatory gynecologic laparoscopy.
Anesth Analg 1996; 83: 975 81
25 Moiniche S, Romsing J, Dahl JB, Tramer MR. Nonsteroidal antiinflammatory drugs and the risk of operative site bleeding after
tonsillectomy: a quantitative systematic review. Anesth Analg
2003; 96: 68 77, table of contents
26 Polati E, Verlato G, Finco G, et al. Ondansetron versus metoclopramide in the treatment of postoperative nausea and vomiting.
Anesth Analg 1997; 85: 395 9
27 Gan TJ, Joshi GP, Viscusi E, et al. Preoperative parenteral parecoxib and follow-up oral valdecoxib reduce length of stay and
improve quality of patient recovery after laparoscopic cholecystectomy surgery. Anesth Analg 2004; 98: 1665 73, table of
contents
28 Roberts GW, Bekker TB, Carlsen HH, Moffatt CH, Slattery PJ,
McClure AF. Postoperative nausea and vomiting are strongly
influenced by postoperative opioid use in a dose-related
manner. Anesth Analg 2005; 101: 13438
29 Habib AS, White WD, Eubanks S, Pappas TN, Gan TJ. A randomized
comparison
of
a
multimodal
management
strategy versus combination antiemetics for the prevention of
postoperative nausea and vomiting. Anesth Analg 2004; 99:
77 81
30 Van den Bosch JE, Moons KG, Bonsel GJ, Kalkman CJ. Does
measurement of preoperative anxiety have added value for predicting postoperative nausea and vomiting? Anesth Analg 2005;
100: 1525 32, table of contents
31 Eberhart LH, Geldner G, Kranke P, et al. The development and
validation of a risk score to predict the probability of postoperative vomiting in pediatric patients. Anesth Analg 2004;
99: 1630 7, table of contents
32 Honkavaara P. Effect of ondansetron on nausea and vomiting
after middle ear surgery during general anaesthesia. Br J
Anaesth 1996; 76: 3168
33 Liu K, Hsu CC, Chia YY. The effect of dose of dexamethasone for
antiemesis after major gynecological surgery. Anesth Analg
1999; 89: 13168
34 Henzi I, Sonderegger J, Tramer MR. Efficacy, dose response, and
adverse effects of droperidol for prevention of postoperative
nausea and vomiting. Can J Anaesth 2000; 47: 53751
35 White PF. Prevention of postoperative nausea and vomitinga
multimodal solution to a persistent problem. N Engl J Med
2004; 350: 25112

BJA

BJA
53

54

55

56

57

58

60

61

62

63

64

65

66

67

68

69

i38

70 Beauregard L, Pomp A, Choiniere M. Severity and impact of pain


after day-surgery. Can J Anaesth 1998; 45: 30411
71 Perkins FM, Kehlet H. Chronic pain as an outcome of surgery. A
review of predictive factors. Anesthesiology 2000; 93: 1123 33
72 Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk
factors and prevention. Lancet 2006; 367: 1618 25
73 Watcha MF, White PF. Postoperative nausea and vomiting. Its
etiology, treatment, and prevention. Anesthesiology 1992; 77:
162 84
74 Chung F. Recovery pattern and home-readiness after ambulatory surgery. Anesth Analg 1995; 80: 896902
75 Kehlet H, Dahl JB. The value of multimodal or balanced analgesia in postoperative pain treatment. Anesth Analg 1993; 77:
104856
76 Eriksson H, Tenhunen A, Korttila K. Balanced analgesia improves
recovery and outcome after outpatient tubal ligation. Acta
Anaesthesiol Scand 1996; 40: 151 5
77 Dahl JB, Kehlet H. Non-steroidal anti-inflammatory drugs: rationale for use in severe postoperative pain. Br J Anaesth
1991; 66: 703 12
78 Blackburn A, Stevens JD, Wheatley RG, Madej TH, Hunter D.
Balanced analgesia with intravenous ketorolac and patientcontrolled morphine following lower abdominal surgery. J Clin
Anesth 1995; 7: 103 8
79 Chan A, Dore CJ, Ramachandra V. Analgesia for day surgery.
Evaluation of the effect of diclofenac given before or after
surgery with or without bupivacaine infiltration. Anaesthesia
1996; 51: 592 5
80 Sutters KA, Levine JD, Dibble S, Savedra M, Miaskowski C. Analgesic efficacy and safety of single-dose intramuscular ketorolac
for postoperative pain management in children following tonsillectomy. Pain 1995; 61: 145 53
81 Nikolajsen L, Sorensen HC, Jensen TS, Kehlet H. Chronic pain following Caesarean section. Acta Anaesthesiol Scand 2004; 48:
111 6
82 Caumo W, Schmidt AP, Schneider CN, et al. Preoperative predictors of moderate to intense acute postoperative pain in patients
undergoing abdominal surgery. Acta Anaesthesiol Scand 2002;
46: 1265 71
83 Katz J, Poleshuck EL, Andrus CH, et al. Risk factors for acute pain
and its persistence following breast cancer surgery. Pain 2005;
119: 16 25
84 Caumo W, Hidalgo MP, Schmidt AP, et al. Effect of pre-operative
anxiolysis on postoperative pain response in patients undergoing total abdominal hysterectomy. Anaesthesia 2002; 57: 740 6
85 Kain ZN, Sevarino FB, Rinder C, et al. Preoperative anxiolysis and
postoperative recovery in women undergoing abdominal hysterectomy. Anesthesiology 2001; 94: 415 22
86 Ciccozzi A, Marinangeli F, Colangeli A, et al. Anxiolysis and postoperative pain in patients undergoing spinal anesthesia for abdominal hysterectomy. Minerva Anestesiol 2007; 73: 387 93
87 Bauer KP, Dom PM, Ramirez AM, OFlaherty JE. Preoperative
intravenous midazolam: benefits beyond anxiolysis. J Clin
Anesth 2004; 16: 177 83
88 Stamer UM, Stuber F. Genetic factors in pain and its treatment.
Curr Opin Anaesthesiol 2007; 20: 478 84
89 Mitra S, Sinatra RS. Perioperative management of acute pain in
the opioid-dependent patient. Anesthesiology 2004; 101:
212 27
90 Kalkman CJ, Visser K, Moen J, Bonsel GJ, Grobbee DE, Moons KG.
Preoperative prediction of severe postoperative pain. Pain 2003;
105: 415 23

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

59

morphine side effects: meta-analysis of randomized controlled


trials. Anesthesiology 2005; 102: 1249 60
Salman MA, Yucebas ME, Coskun F, Aypar U. Day-case laparoscopy: a comparison of prophylactic opioid, NSAID or local anesthesia for postoperative analgesia. Acta Anaesthesiol Scand
2000; 44: 536 42
Camu F, Beecher T, Recker DP, Verburg KM. Valdecoxib, a COX-2specific inhibitor, is an efficacious, opioid-sparing analgesic in
patients undergoing hip arthroplasty. Am J Ther 2002; 9: 43 51
Subramaniam K, Subramaniam B, Steinbrook RA. Ketamine as
adjuvant analgesic to opioids: a quantitative and qualitative systematic review. Anesth Analg 2004; 99: 48295, table of
contents
Bell RF, Dahl JB, Moore RA, Kalso E. Perioperative ketamine for
acute postoperative pain. Cochrane Database Syst Rev 2006;
CD004603
Cheng CR, Sessler DI, Apfel CC. Does neostigmine administration
produce a clinically important increase in postoperative nausea
and vomiting? Anesth Analg 2005; 101: 134955
Kranke P, Schuster F, Eberhart LH. Recent advances, trends and
economic considerations in the risk assessment, prevention and
treatment of postoperative nausea and vomiting. Expert Opin
Pharmacother 2007; 8: 3217 35
McKenzie R, Uy NT, Riley TJ, Hamilton DL. Droperidol/ondansetron combination controls nausea and vomiting after tubal
banding. Anesth Analg 1996; 83: 1218 22
Riley TJ, McKenzie R, Trantisira BR, Hamilton DL. Droperidol
ondansetron combination versus droperidol alone for postoperative control of emesis after total abdominal hysterectomy.
J Clin Anesth 1998; 10: 612
Hache JJ, Vallejo MC, Waters JH, Williams BA. Aprepitant in
a multimodal approach for prevention of postoperative
nausea and vomiting in high-risk patients: is there such a
thing as too many modalities? ScientificWorldJournal 2009; 9:
291 9
Glass PS, White PF. Practice guidelines for the management of
postoperative nausea and vomiting: past, present, and future.
Anesth Analg 2007; 105: 1528 9
Fan CF, Tanhui E, Joshi S, Trivedi S, Hong Y, Shevde K. Acupressure treatment for prevention of postoperative nausea and
vomiting. Anesth Analg 1997; 84: 821 5
Zarate E, Mingus M, White PF, et al. The use of transcutaneous
acupoint electrical stimulation for preventing nausea and
vomiting after laparoscopic surgery. Anesth Analg 2001; 92:
629 35
Helmreich RJ, Shiao SY, Dune LS. Meta-analysis of acustimulation effects on nausea and vomiting in pregnant women.
Explore (NY) 2006; 2: 41221
White PF, Issioui T, Hu J, et al. Comparative efficacy of acustimulation (ReliefBand) versus ondansetron (Zofran) in combination
with droperidol for preventing nausea and vomiting. Anesthesiology 2002; 97: 107581
Streitberger K, Diefenbacher M, Bauer A, et al. Acupuncture compared to placebo-acupuncture for postoperative nausea and
vomiting prophylaxis: a randomised placebo-controlled patient
and observer blind trial. Anaesthesia 2004; 59: 142 9
Rawal N, Hylander J, Nydahl PA, Olofsson I, Gupta A. Survey of
postoperative analgesia following ambulatory surgery. Acta
Anaesthesiol Scand 1997; 41: 1017 22
Rathmell JP, Wu CL, Sinatra RS, et al. Acute post-surgical pain
management: a critical appraisal of current practice, December
2 4, 2005. Reg Anesth Pain Med 2006; 31(4 Suppl. 1): 1 42

Chandrakantan and Glass

Multimodal therapies for PONV and pain

109 Romsing J, Moiniche S. A systematic review of COX-2 inhibitors


compared with traditional NSAIDs, or different COX-2 inhibitors
for post-operative pain. Acta Anaesthesiol Scand 2004; 48:
525 46
110 White PF, Kehlet H, Liu S. Perioperative analgesia: what do we
still know? Anesth Analg 2009; 108: 1364 7
111 Nussmeier NA, Whelton AA, Brown MT, et al. Safety and efficacy
of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib
after noncardiac surgery. Anesthesiology 2006; 104: 51826
112 White PF, Tang J, Wender RH, et al. The effects of oral ibuprofen
and celecoxib in preventing pain, improving recovery outcomes
and patient satisfaction after ambulatory surgery. Anesth Analg
2010; 112: 323 9
113 Menigaux C, Guignard B, Fletcher D, Sessler DI, Dupont X,
Chauvin M. Intraoperative small-dose ketamine enhances analgesia after outpatient knee arthroscopy. Anesth Analg 2001; 93:
606 12
114 Lavandhomme P, De Kock M, Waterloos H. Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing major digestive
surgery. Anesthesiology 2005; 103: 81320
115 Chia YY, Liu K, Liu YC, Chang HC, Wong CS. Adding ketamine in a
multimodal patient-controlled epidural regimen reduces postoperative pain and analgesic consumption. Anesth Analg
1998; 86: 1245 9
116 Hocking G, Cousins MJ. Ketamine in chronic pain management:
an evidence-based review. Anesth Analg 2003; 97: 17309
117 Seib RK, Paul JE. Preoperative gabapentin for postoperative analgesia: a meta-analysis. Can J Anaesth 2006; 53: 4619
118 Kong VK, Irwin MG. Gabapentin: a multimodal perioperative
drug? Br J Anaesth 2007; 99: 77586
119 Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H,
Dahl JB. A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology 2002; 97: 560 4
120 Clarke H, Pereira S, Kennedy D, et al. Adding gabapentin to a
multimodal regimen does not reduce acute pain, opioid consumption or chronic pain after total hip arthroplasty. Acta
Anaesthesiol Scand 2009; 53: 1073 83
121 Nikolajsen L, Finnerup NB, Kramp S, Vimtrup AS, Keller J,
Jensen TS. A randomized study of the effects of gabapentin
on postamputation pain. Anesthesiology 2006; 105: 100815
122 Buvanendran A, Kroin JS, Della Valle CJ, Kari M, Moric M,
Tuman KJ. Perioperative oral pregabalin reduces chronic pain
after total knee arthroplasty: a prospective, randomized, controlled trial. Anesth Analg 2010; 110: 199 207
123 Amr YM, Yousef AA. Evaluation of efficacy of the perioperative
administration of Venlafaxine or gabapentin on acute and
chronic postmastectomy pain. Clin J Pain 2010; 26: 381 5
124 Lin TF, Yeh YC, Lin FS, et al. Effect of combining dexmedetomidine and morphine for intravenous patient-controlled analgesia.
Br J Anaesth 2009; 102: 117 22
125 Arain SR, Ruehlow RM, Uhrich TD, Ebert TJ. The efficacy of dexmedetomidine versus morphine for postoperative analgesia
after major inpatient surgery. Anesth Analg 2004; 98: 1538,
table of contents
126 Tufanogullari B, White PF, Peixoto MP, et al. Dexmedetomidine
infusion during laparoscopic bariatric surgery: the effect on recovery outcome variables. Anesth Analg 2008; 106: 17418
127 Jeffs SA, Hall JE, Morris S. Comparison of morphine alone with
morphine plus clonidine for postoperative patient-controlled
analgesia. Br J Anaesth 2002; 89: 4247

i39

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

91 Rosaeg OP, Lui AC, Cicutti NJ, Bragg PR, Crossan ML, Krepski B.
Peri-operative multimodal pain therapy for caesarean section:
analgesia and fitness for discharge. Can J Anaesth 1997; 44:
803 9
92 Fassoulaki A, Triga A, Melemeni A, Sarantopoulos C. Multimodal
analgesia with gabapentin and local anesthetics prevents acute
and chronic pain after breast surgery for cancer. Anesth Analg
2005; 101: 142732
93 Costigan M, Scholz J, Woolf CJ. Neuropathic pain: a maladaptive
response of the nervous system to damage. Annu Rev Neurosci
2009; 32: 1 32
94 Staud R, Craggs JG, Robinson ME, Perlstein WM, Price DD. Brain
activity related to temporal summation of C-fiber evoked pain.
Pain 2007; 129: 13042
95 Labrakakis C, Ferrini F, Koninck Y. Mechanisms of plasticity of inhibition in chronic pain conditions. In: Woodin MA, Maffei A, eds.
Inhibitory Synaptic Plasticity. New York: Springer, 2011; 91 105
96 Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in
neuropathic pain: diagnosis, mechanisms, and treatment
recommendations. Arch Neurol 2003; 60: 1524 34
97 Pogatzki-Zahn EM, Zahn PK. From preemptive to preventive analgesia. Curr Opin Anaesthesiol 2006; 19: 5515
98 Katz J, McCartney CJ. Current status of preemptive analgesia.
Curr Opin Anaesthesiol 2002; 15: 435 41
99 Capdevila X, Barthelet Y, Biboulet P, Ryckwaert Y, Rubenovitch J,
dAthis F. Effects of perioperative analgesic technique on the
surgical outcome and duration of rehabilitation after major
knee surgery. Anesthesiology 1999; 91: 815
100 Barratt SM, Smith RC, Kee AJ, Mather LE, Cousins MJ. Multimodal
analgesia and intravenous nutrition preserves total body protein
following major upper gastrointestinal surgery. Reg Anesth Pain
Med 2002; 27: 1522
101 White PF. The changing role of non-opioid analgesic techniques
in the management of postoperative pain. Anesth Analg 2005;
101(5 Suppl.): S5 22
102 Oderda GM, Evans RS, Lloyd J, et al. Cost of opioid-related
adverse drug events in surgical patients. J Pain Symptom
Manage 2003; 25: 27683
103 Gupta K, Kshirsagar S, Chang L, et al. Morphine stimulates
angiogenesis by activating proangiogenic and survivalpromoting signaling and promotes breast tumor growth.
Cancer Res 2002; 62: 44918
104 Singleton PA, Moss J. Effect of perioperative opioids on cancer
recurrence: a hypothesis. Future Oncol 2010; 6: 123742
105 Biki B, Mascha E, Moriarty DC, Fitzpatrick JM, Sessler DI,
Buggy DJ. Anesthetic technique for radical prostatectomy
surgery affects cancer recurrence: a retrospective analysis.
Anesthesiology 2008; 109: 1807
106 Exadaktylos AK, Buggy DJ, Moriarty DC, Mascha E, Sessler DI.
Can anesthetic technique for primary breast cancer surgery
affect recurrence or metastasis? Anesthesiology 2006; 105:
660 4
107 Elia N, Lysakowski C, Tramer MR. Does multimodal analgesia
with acetaminophen, nonsteroidal antiinflammatory drugs, or
selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone?
Meta-analyses of randomized trials. Anesthesiology 2005; 103:
1296 304
108 Marret E, Flahault A, Samama CM, Bonnet F. Effects of postoperative, nonsteroidal, antiinflammatory drugs on bleeding
risk after tonsillectomy: meta-analysis of randomized, controlled trials. Anesthesiology 2003; 98: 1497 502

BJA

BJA

i40

138 Jensen MK, Andersen C. Can chronic poststernotomy pain after


cardiac valve replacement be reduced using thoracic epidural
analgesia? Acta Anaesthesiol Scand 2004; 48: 8714
139 Brandsborg B, Nikolajsen L, Hansen CT, Kehlet H, Jensen TS. Risk
factors for chronic pain after hysterectomy: a nationwide questionnaire and database study. Anesthesiology 2007; 106:
1003 12
140 Chan MT, Wan AC, Gin T, Leslie K, Myles PS. Chronic postsurgical pain after nitrous oxide anesthesia. Pain 2011; 152:
2514 20
141 Paech MJ, Pavy TJ, Orlikowski CE, Lim W, Evans SF. Postoperative
epidural infusion: a randomized, double-blind, dose-finding trial
of clonidine in combination with bupivacaine and fentanyl.
Anesth Analg 1997; 84: 1323 8
142 Wallet F, Clement HJ, Bouret C, et al. Effects of a
continuous low-dose clonidine epidural regimen on pain, satisfaction and adverse events during labour: a randomized,
double-blind, placebo-controlled trial. Eur J Anaesthesiol
2010; 27: 4417
143 Curatolo M, Schnider TW, Petersen-Felix S, et al. A direct search
procedure to optimize combinations of epidural bupivacaine,
fentanyl, and clonidine for postoperative analgesia. Anesthesiology 2000; 92: 325 37
144 Bjordal JM, Johnson MI, Ljunggreen AE. Transcutaneous electrical nerve stimulation (TENS) can reduce postoperative analgesic
consumption. A meta-analysis with assessment of optimal
treatment parameters for postoperative pain. Eur J Pain 2003;
7: 1818
145 Fountas KN, Kapsalaki EZ, Johnston KW, Smisson HF III,
Vogel RL, Robinson JS Jr. Postoperative lumbar microdiscectomy
pain. Minimalization by irrigation and cooling. Spine (Phila Pa
1976) 1999; 24: 195860
146 Werner MU, Duun P, Kehlet H. Prediction of postoperative pain
by preoperative nociceptive responses to heat stimulation.
Anesthesiology 2004; 100: 1159, discussion 115A
147 Maletic V, Raison CL. Neurobiology of depression,
fibromyalgia and neuropathic pain. Front Biosc 2009; 14:
5291 338
148 Costigan M, Woolf CJ. Pain: molecular mechanisms. J Pain 2000;
1(Suppl. 1): 35 44

Downloaded from http://bja.oxfordjournals.org/ by guest on May 31, 2014

128 Striebel WH, Koenigs DI, Kramer JA. Intravenous clonidine fails
to reduce postoperative meperidine requirements. J Clin
Anesth 1993; 5: 2215
129 Jahangiri M, Jayatunga AP, Bradley JW, Dark CH. Prevention of
phantom pain after major lower limb amputation by epidural infusion of diamorphine, clonidine and bupivacaine. Ann R Coll
Surg Engl 1994; 76: 3246
130 Michaloliakou C, Chung F, Sharma S. Preoperative multimodal
analgesia facilitates recovery after ambulatory laparoscopic
cholecystectomy. Anesth Analg 1996; 82: 44 51
131 Bisgaard T, Klarskov B, Kristiansen VB, et al. Multi-regional local
anesthetic infiltration during laparoscopic cholecystectomy in
patients receiving prophylactic multi-modal analgesia: a randomized, double-blinded, placebo-controlled study. Anesth Analg
1999; 89: 1017 24
132 Klein SM, Nielsen KC, Greengrass RA, Warner DS, Martin A,
Steele SM. Ambulatory discharge after long-acting peripheral
nerve blockade: 2382 blocks with ropivacaine. Anesth Analg
2002; 94: 65 70, table of contents
133 Capdevila X, Pirat P, Bringuier S, et al. Continuous peripheral
nerve blocks in hospital wards after orthopedic surgery: a multicenter prospective analysis of the quality of postoperative analgesia and complications in 1,416 patients. Anesthesiology 2005;
103: 1035 45
134 McCartney CJ, Duggan E, Apatu E. Should we add clonidine to
local anesthetic for peripheral nerve blockade? A qualitative systematic review of the literature. Reg Anesth Pain Med 2007; 32:
330 8
135 Rodgers A, Walker N, Schug S, et al. Reduction of postoperative
mortality and morbidity with epidural or spinal anaesthesia:
results from overview of randomised trials. Br Med J 2000;
321: 1493
136 Brodner G, Van Aken H, Hertle L, et al. Multimodal perioperative
managementcombining thoracic epidural analgesia, forced
mobilization, and oral nutritionreduces hormonal and metabolic stress and improves convalescence after major urologic
surgery. Anesth Analg 2001; 92: 1594600
137 Senturk M, Ozcan PE, Talu GK, et al. The effects of three different
analgesia techniques on long-term postthoracotomy pain.
Anesth Analg 2002; 94: 115, table of contents

Chandrakantan and Glass